Poor glycemic control in diabetes and hypertension can lead to the requirement for hemodialysis. In order to facilitate treatment, a significant number of patients with these disorders will have a synthetic vascular graft surgically implanted between the venous and arterial systems to allow arterial-venous (A-V) access at the implantation type. The average time a synthetic graft will remain useful for A-V access is about two years. During these two years, infection will develop in around 20% of patients, and often leads to graft removal. The hemodialysis access then has to be reestablished. Often, this means finding another site for A-V access and waiting a period of time of three weeks before a normal hemodialysis schedule can be resumed. It is known that 15-30% of all dialysis patients will have infection of their implant as a major cause of death.
There are principally three ways in which an infection can be introduced during A-V access set up or the hemodialysis procedure itself. For example, bacteria can be implanted with the A-V access device itself during a break in aseptic technique. Another way is through the attachment of bacteria which are already internally present onto the surface of the device. Moreover, bacteria can be transmitted from external sources, such as central venous catheters and needles. The major cause in infection involving A-V access PTFE grafts has been shown to be due to a break in aseptic cannulation. The port of entry for infection is typically the puncture site or catheter.
The most common infectious agents are: staphylococcus aureus, pseudomonas aeruginosa, and staphylococcus epidermis. These agents have been identified in over 75% of all reported vascular infections. Both staphylococcus aureus and pseudomonas aeruginosa, show high virulence and can lead to clinical signs of infection early in the post-operative period (less than four months). It is this virulence that leads to septicemia and is one main factor in the high mortality rates. Staphylococcus epidermis is described as a low virulence type of bacterium. It is late occurring, which means it can present clinical signs of infection up to five years post-operative. This type of bacterium has been shown to be responsible for up to 60% of all vascular graft infections. Infections of this type often require total graft excision, debridement of surrounding tissue, and revascularization through an uninfected route.
Such high virulence organisms are usually introduced at the time of implantation. For example, some of the staphylococcus strains (including staphylococcus aureus) have receptors for tissue ligands such as fibrinogen molecules which are among the first deposits seen after implantation of a graft. This tissue ligand binding provides a way for the bacteria to be shielded from the host immune defenses as well as systemic antibiotics. The bacteria can then produce polymers in the form of a polysaccharide that can lead to a slime layer on the outer surface of the graft. In this protective environment, bacterial reproduction occurs and colonies form within the biofilm that can shed cells to surrounding tissues (Calligaro, K. and Veith, Frank, Surgery, 1991 V110-No. 5, 805-811). Infection can also originate from transected lymphatics, from inter-arterial thrombus, or be present within the arterial wall.
There are severe complications as a result of vascular graft infections. For example, anastonomic disruption due to proteolytic enzymes that the more virulent organisms produce can lead to a degeneration of the arterial wall adjacent to the anastomosis. This can lead to a pseudoaneurism which can rupture and cause hemodynamic instability. A further complication of a vascular graft infection can be distal styptic embolisms, which can lead to the loss of a limb, or aortoenteric fistulas, which are the result of a leakage from a graft that is infected and that leads to gastrointestinal bleeding (Greisler, H., Infected Vascular Grafts. Maywood, Ill., 33-36).
Desirably, it would be beneficial to prevent any bacteria from adhering to the graft, or to the immediate area surrounding the graft at the time of implantation. It would further be desirable to prevent the initial bacterial biofilm formation described above by encouraging normal tissue ingrowth within the tunnel, and by protecting the implant itself from the biofilm formation.
Silver has been shown in vitro to inhibit bacterial growth in several ways. For example, it is known that silver can interrupt bacterial growth by interfering with bacterial replication through a binding of the microbial DNA, and also through the process of causing a denaturing and inactivation of crucial microbial metabolic enzymes by binding to the sulfhydryl groups (Tweten, K., J. of Heart Valve Disease 1997, V6, No. 5, 554-561). It is also known that silver causes a disruption of the cell membranes of blood platelets. This increased blood platelet disruption leads to increased surface coverage of the implants with platelet cytoskeletal remains. This process has been shown to lead to an encouragement of the formation of a more structured (mature state) pannus around the implant. This would likely discourage the adhesion and formation of the biofilm produced by infectious bacteria due to a faster tissue ingrowth time (Goodman, S. et al, 24th Annual Meeting of the society for Biomaterials, April 1998, San Diego, Calif.; pg. 207).
It is known to incorporate antimicrobial agents into a medical device. For example, prior art discloses an ePTFE vascular graft, a substantial proportion of the interstices of which contain a coating composition that includes: a biomedical polyurethane; poly(lactic acid), which is a biodegradable polymer; and the anti-microbial agents, chlorhexidine acetate and pipracil. The prior art further describes an ePTFE hernia patch which is impregnated with a composition including silver sulfadiazine and chlorhexidine acetate and poly(lactic acid).
Further prior art describes a medical implant wherein an antimicrobial agent penetrates the exposed surfaces of the implant and is impregnated throughout the material of the implant. The medical implant may be a vascular graft and the material of the implant may be polytetrafluoroethylene (PTFE). The antimicrobial agent is selected from antibiotics, antiseptics and disinfectants.
Moreover, there is prior art that discloses that silver, which is a known antiseptic agent, can be deposited onto the surface of a porous polymeric substrate via silver, ion assisted beam deposition prior to filling the pores of the porous polymeric material with an insoluble, biocompatible, biodegradable material. This prior art further discloses that antimicrobials can be integrated into the pores of the polymeric substrate. The substrate may be a porous vascular graft of ePTFE.
It is known that multiple layers in grafts can be effective in providing a differential cross-section of permeability and/or porosity to achieve enhanced healing and tissue ingrowth. In addition, attempts to increase the radial tensile and axial tear strengths of porous tubular grafts include placing multiple layers over one another. Prior art describing composite, anti-infective medical devices will now be discussed.
It is known to provide an anti-infective medical article including a hydrophilic polymer having silver chloride bulk distributed therein. The hydrophilic polymer may be a laminate over a base polymer. Preferred hydrophilic polymers are disclosed as melt processible polyurethanes. The medical article may be a vascular graft. A disadvantage of this graft is that it is not formed of ePTFE, which is known to have natural antithrombogenic properties. A further disadvantage is that the hydrophilic polyurethane matrix into which the silver salt is distributed does not itself control the release of silver into the surrounding body fluid and tissue at the implantation site of the graft.
Furthermore, there is prior art describing an implantable medical device that can include a stent structure, a layer of bioactive material posited on one surface of the stent structure, and a porous polymeric layer for controlled release of a bioactive material which is posited over the bioactive material layer. The thickness of the porous polymeric layer is described as providing this controlled release. The medical device can further include another polymeric coating layer between the stent structure and the bioactive material layer. This polymeric coating layer is disclosed as preferably being formed of the same polymer as the porous polymeric layer. Silver can be included as the stent base metal or as a coating on the stent base metal. Alternatively, silver can be in the bioactive layer or can be posited on or impregnated in the surface matrix of the porous polymeric layer. Polymers of polytetrafluoroethylene and bioabsorbable polymers can be used. A disadvantage of this device is that the porous polymeric outer layer needs to be applied without the use of solvents, catalysts, heat or other chemicals or techniques, which would otherwise degrade or damage the bioactive agent deposited on the surface of the stent. Moreover, this graft is not designed to achieve fast tissue ingrowth within the tunnel to discourage initial bacterial biofilm formation.
Further prior art describes a vascular graft made with a porous antimicrobial fabric formed by fibers which are laid transverse to each other, and which define pores between the fibers. The fibers may be of ePTFE. Ceramic particles are bound to the fabric material, the particles including antimicrobial metal cations thereon, which may be silver ions. The ceramic particles are exteriorly exposed and may be bound to the graft by a polymeric coating material, which may be a biodegradable polymer. A disadvantage of this device is that the biodegradable coating layer does not provide sufficient tensile strength for an outer graft layer. Moreover, this graft does not include a polymeric ePTFE tube, which has certain advantages over conventional textile prostheses. For example, a polymeric ePTFE tube has a microporous structure consisting of small nodes interconnected with many thin fibrils. The diameter of the fibrils, which depend on the processing conditions, can be controlled to a large degree, and the resulting flexible structure has greater versatility. For example, it can be used in both large diameter, i.e. 6 mm or greater artificial blood vessels, as well as in grafts having diameters of 5 mm or less.
There is a need for additional antimicrobial vascular grafts formed of ePTFE. In particular, there is a need for ePTFE multi-layered vascular grafts which incorporate antimicrobial agents that can be controllably released from biodegradable materials in the graft to suppress infection following implantation and to prevent biofilm formation. It would also be desirable to provide such grafts with sufficient tensile strength in the tissue-contacting outer layer and with good cellular communication between the blood and the perigraft tissue in the luminal layer.